Neuropathic pain is a complex, chronic pain state that is usually initiated by tissue injury and maintained, in part, by subsequent dysfunction of damaged peripheral nerve fibers or fibers that innervate that injured tissue. The impact of nerve fiber damage includes a change in nerve function both at the site of injury and areas around the injury. Certain types of peripheral nerve damage cause the development of neuromas with associated localized chronic pain manifested as allodynia and hyperalgesia. Approximately 30% of these neuromas become sufficiently painful that the affected digit, hand or limb becomes excluded from activities of daily living and the patient is unable to complete routine tasks. Neuroma pain is particularly difficult to treat, and generally responds poorly to current neuropathic pain treatments. The exact pathophysiology of this neuroma pain is poorly understood, though peripheral and central sensitization has been speculated. Calcitonin Gene-Related Peptide (CGRP) appears to be critical in this process. CGRP is synthesized by nociceptive sensory neurons of dorsal root ganglia (DRG) and released both in the spinal cord where the peptide sensitizes secondary neurons, and from peripheral nerve endings. The effects of CGRP release in the periphery are multifaceted, including induction of vasodilation and macrophage recruitment. Expression of CGRP increases in the DRG neurons of rats after peripheral nerve injury and CGRP accumulates in experimentally-induced neuromas in rats as well as in human neuromas. Furthermore, excessive release of CGRP into the skin of rats was demonstrated in experimentally-induced diabetic neuropathy. These results suggest that increases in CGRP synthesis and release are important in at least some types of neuropathic pain and may specifically be involved in neuroma pain. The most potent and selective CGRP receptor antagonist, CGRP8-37, is a large peptide and cannot be easily delivered to neurogenic inflammatory sites by common routes. To overcome this problem, we have developed and utilized innovative dissolvable CGRP8-37 microneedle technology and completed a feasibility study of their analgesic potential with SBIR Phase I support (R43 DA026363). In this study, we demonstrated that microneedle delivery of CGRP8-37 or a combination of CGRP8-37 and a Na+ channel blocker to the skin, successfully blocked neurogenic inflammatory pain after ultraviolet B irradiation (UVB) of the skin of rats. In the SBIR Phase II studies proposed here, we will focus on evaluation of microneedle efficacy in two clinically applicable animal models of neuropathic pain - the spared nerve injury model and the tibial neuroma transposition model. Toward the development of an IND application, we will also investigate the microneedle safety in rabbits which have higher skin sensitivity than rats. The Specific Aims are as follows: 1. Test the efficacy of CGRP8-37 microneedle patches in two rat neuropathic pain models: the Spared Nerve Injury model of regional pain and a more localized neuropathic model, the Tibial Neuroma Transposition model. 2. Investigate local dermal toxicity following the transdermal application of microneedles in rats and rabbits, and evaluate toxicity following systemic administration of CGRP8-37 in rats. 3. Examine means of optimizing manufacturing processes of microneedle patches in order to prepare for future IND studies. This Phase II project, if successful, will provide an evidence-based go/no go decision toward IND enabling studies that can lead to first-in-human testing of CGRP8-37 microneedles in volunteers and patients supported by competitive renewal of this Phase II SBIR project. PUBLIC HEALTH RELEVANCE: Neuropathic pain has an annual incidence of almost 1% of the general population Neuropathic pain is frequently regional or localized and frequently follows tissue trauma or nerve injury. Our SBIR Phase I and new preliminary studies demonstrated that cutaneous application of dissolvable microneedles containing a peptide antagonist of the calcitonin gene related peptide receptor is effective in treatment of neurogenic inflammatory and neuropathic pain. In this Phase II study, we aim to further develop this innovative approach as a safe, effective, and convenient therapy for the treatment of regional or localized neuropathic pain.